This invention relates generally to powder handling apparatus and methods, and more particularly to a system for efficient preparation and handling of powdered mixtures.
Automated powder dispensing systems are used in many laboratory and commercial applications. In the pharmaceutical industry, for example, such systems are used to fill capsules with small but accurate doses of drugs, typically using gravimetric or volumetric techniques. These systems suffer various disadvantages, including an inability to handle a wide range of particulate materials at optimal speeds and accuracies, particularly when very small doses are involved (e.g., 20 mg or less). Further, the operation of conventional systems tends to crush the particles being handled.
Automated powder handling systems also have application to combinatorial (high-throughput) research. For example, they can be used for combinatorial catalysis research where catalyst candidates are evaluated using various screening techniques known in the art. See, for example, U.S. Pat. No. 5,985,356 to Schultz et al., U.S. Pat. No. 6,004,617 to Schultz et al., U.S. Pat. No. 6,030,917 to Weinberg et al., U.S. Pat. No. 5,959,297 to Weinberg et al., U.S. Pat. No. 6,149,882 to Guan et al., U.S. Pat. No. 6,087,181 to Cong, U.S. Pat. No. 6,063,633 to Willson, U.S. Pat. No. 6,175,409 to Nielsen et al., and PCT patent to Willson, U.S. Pat. No. 6,175,409 to Nielsen et al., and PCT patent applications WO 00/09255, WO 00/17413, WO 00/51720, WO 00/14529, each of which U.S. patents and each of which PCT patent applications, together with its corresponding U.S. application(s), is hereby incorporated by reference in its entirety for all purposes.
The efficiency of a combinatorial chemistry discovery program is, in general, limited by rate-limiting steps of the overall process work flow. One such rate-limiting step has been the mechanical pretreatment and handling of catalyst candidates after synthesis but before screening. U.S. application Ser. No. 902,552, filed Jul. 9, 2001 by Lugmair, et al., published Feb. 7, 2002 as Pub. No. US 2002/0014546 A1, and assigned to Symyx Technologies, Inc., incorporated herein by reference in its entirety for all purposes, is directed to more efficient protocols and systems for effecting the mechanical treatment of materials, and especially, mechanical treatment of catalysis materials such as heterogeneous catalysts and related materials. The disclosed protocols provide an efficient way to prepare catalysis materials having a controlled particle size for optimal screening. However, the handling and transfer of such powders from one location to another as they are prepared for screening and ultimately delivered to the screening device (e.g., a parallel flow reactor) is not addressed in detail. The circumstances are similar in the pharmaceutical industry. For example, processes used to screen one or more excipients (i.e., diluents, pH modifiers, viscosity modifiers, stabilizers, flavorings, colorings, fillers and combinations thereof) for suitability for use with one or more active pharmaceutical ingredients can involve preparation and handling of powdered samples. Commonly assigned U.S. application Ser. No. 10/790,956 entitled “Evaluating Effects of Exposure Conditions on Drug Samples Over Time” filed Mar. 1, 2004, hereby incorporated by reference in its entirety for all purposes, describes forced degradation testing of excipients. That disclosure sets forth detailed analytic methods for using combinatorial chemistry to screen powdered excipients, but does not address powder handling in detail. Similar methods can be used to screen the compatibility of one powdered active ingredient with one or more other powdered active ingredients. Likewise, combinatorial chemistry can be applied to the creation and testing of various powdered polymorphs of drug candidates, such as is described in commonly assigned PCT application No. WO 03/014732, hereby incorporated by reference in its entirety for all purposes. That disclosure refers to screening powdered samples without discussing any powder handling systems in detail.
In some cases two or more different powders, such as an active ingredient and one or more excipients, are mixed together for further analysis. Many powder handling systems are based on the premise that any powdered ingredients in a sample will be dissolved in a solution, thereby obviating the need to mix powdered ingredients in their powdered form. But some research requires the powders to be maintained in solid form for testing. For example, a powdered mixture may be formed into a tablet for pharmaceutical testing. It may also be desirable to maintain a powdered mixture in solid form to conduct various spectroscopic, X-ray, or other solid-phase analyses.
A stirrer, such as the end of a pipette, a stirring bar, or a milling ball can be used to mix powders. Unfortunately, removal of the stirrer after mixing can alter the sample composition because one powder may have more or less affinity for the stirrer than other powders in the sample. Consequently, removal of the stirrer risks disproportionate removal of one or more powders in a residue on the stirrer. When the sample size is small, as is typically the case in combinatorial chemistry, the problem is exacerbated because disproportionate removal of relatively smaller amounts of powder significantly alters the overall sample composition. Thus, it is common practice to leave at least the portion of the stirrer that contacts the powder in the sample to avoid removal of any residue. For example, the tip of a pipette can be broken off and left in the sample container. Likewise, stirring bars and milling balls are often left in the sample after mixing. Not only does this consume the stirrer, but there is also a chance that the continuing presence of the stirrer could affect the sample analysis or limit the types of analyses that can be performed. Furthermore, if mixed powder samples are to be pressed into tablets for ingestion (e.g., in a pharmaceutical trial), it would be preferable not to have foreign objects like milling balls and pipette tips in the tablets.
Similar rate limiting steps and/or the need to mix powders can arise whenever a process requires preparation and handling of powdered materials. This can be the case during synthesis or screening of pharmaceuticals and catalysts (as already mentioned) as well as agricultural chemicals, pigments, and flavorings to name just a few of the other applications for powder handling systems.